The Zurich Cohort Study is a prospective longitudinal study of a cohort of young adults from Zurich, Switzerland, who were followed from the ages of 20-40 in order to estimate the prevalence, incidence, impairment, treatment patterns and stability of the major mental disorders. This study assessed a wide range of psychiatric syndromes as well as somatic syndromes including mild manifestations under the conventional diagnostic thresholds (Angst et al 1984). The Zurich cohort study is comprised of a cohort of 4,547 subjects (m=2201; f = 2346) representative of the canton of Zurich in Switzerland, who were screened in 1978 with the Symptom Checklist 90-R (Derogatis 1988). In order to enrich the probability of psychiatric syndromes, a sub-sample of 591 subjects (291 males, 299 females) was selected for interview, with two thirds consisting of high scorers (defined by the 85th percentile or more of the SCL-90) and a random sample of those with scores below the 85th percentile. There have been a total of 6 waves of interviews covering the age period of 20-40 years. Those who had dropped out did not differ significantly in their baseline measures in terms of demographic characteristics, or risk group at study entry. A direct interview, the Structured Psychopathological Interview and Rating of the Social Consequences for Epidemiology (SPIKE), was administered by psychiatric residents and clinical psychologists with extensive clinical training in the subjects' homes. This interview schedule assesses a number of somatic syndromes, including headache, gastrointestinal, cardiovascular, and respiratory syndromes, as well as psychological syndromes, including depression, anxiety, phobia, obsessive-compulsive disorder, and substance abuse. Rather than adhering to a single diagnostic classification system, the entire spectrum of symptoms and correlates were assessed. Other measures included a personal and family history of all syndromes, dimensional measures of impairment and distress, personality traits, and other relevant constructs. Comorbid anxiety and depression tended to be far more persistent than either syndrome alone. Individuals with anxiety states alone tended to develop either depression alone or comorbid anxiety and depression as they progressed through adulthood. In contrast, depression alone and that which was comorbid with anxiety tended to be far more stable than anxiety alone over time. These findings have important implications for classification and treatment of affective disorders. The greater stability of comorbid anxiety and depression than either disorder alone illustrates the importance of further investigation of comorbid states compared to non-comorbid states in etiologic and treatment research. The persistence of subthreshold level depression and anxiety from early- to mid- adulthood suggests the importance of characterizing the continuum of expression of depression and anxiety rather than adhering to strict diagnostic thresholds. At the NIMH, we have continued to use the Zurich Study data to test the thresholds and boundaries of affective and anxiety disorders, disease subtypes, and the longitudinal patterns of expression of these conditions. Several important findings from this unique study have guided the methodologic developments and substantive research in our other population surveys as well as in our more intensive family studies. The chief findings are that the atypical subtype of depression is a valid entity that is more strongly associated with bipolar spectrum disorder than non-atypical major depression; that reverse vegetative symptoms (increased sleeping and eating) and extreme fatigue are the core features of this subtype, and the other proposed criteria of mood reactivity and rejection sensitivity, do not yield a more valid diagnostic category; there is also a characteristic developmental sequence of anxiety and depression such that anxiety is often followed by depression, whereas the onset of anxiety rarely occurs after that of depression; both anxiety and depression tend to be chronic conditions, with only a small minority of people in the population having single episodes across the life span. Our findings support the use of a more dimensional conception of the symptom clusters combined with orthogonal ratings of the indicators of severity or impairment. We also observed that people with bipolar II disorder have a 10-fold increased risk for the development of alcohol abuse and 20-fold increased risk for alcohol dependence across 20 years of follow up). This latter finding has important implications for studies of bipolar disorder both in terms of misclassification of underlying bipolarity in people with alcohol dependence, and the specificity of alcohol use to ameliorate symptoms of mania. This work suggests that the need for a major shift in our conceptualization of mood and anxiety disorders which tend to be more accurately represented by dimensions than categories. Second, the lack of inclusion of atypical features as a subtype of depression, particularly its association with bipolar spectrum disorder, is a major omission that could compromise genetic, biologic and treatment studies of mood disorders. Third, the strong concurrent and longitudinal overlap between mood and anxiety syndromes suggests that future studies should explore the genetic and other biologic mechanisms for their co-occurrence and developmental sequence. The findings highlight the importance of prospective longitudinal research in validating diagnostic concepts, characterizing clinical course and identifying etiologic pathways in psychiatry.